title: Dynamic association of tau with neuronal membranes is regulated by phosphorylation.
abstract: Tau is an abundant cytosolic protein which regulates cytoskeletal stability by associating with microtubules in a phosphorylation-dependent manner. We have found a significant proportion of tau is located in the membrane fraction of rat cortical neurons and is dephosphorylated, at least at Tau-1 (Ser199/Ser202), AT8 (Ser199/Ser202/Thr205) and PHF-1 (Ser396/Ser404) epitopes. Inhibition of tau kinases casein kinase 1 (CK1) or glycogen synthase kinase-3 decreased tau phosphorylation and significantly increased amounts of tau in the membrane fraction. Mutation of serine/threonine residues to glutamate to mimic phosphorylation in the N-terminal, but not C-terminal, region of tau prevented its membrane localization in transfected cells, demonstrating that the phosphorylation state of tau directly impacts its localization. Inhibiting CK1 in neurons lacking the tyrosine kinase fyn also induced tau dephosphorylation but did not affect its membrane association. Furthermore, inhibition of CK1 increased binding of neuronal tau to the fyn-SH3 domain. We conclude that trafficking of tau between the cytosol and the neuronal membrane is dynamically regulated by tau phosphorylation through a mechanism dependent on fyn expression.
authors.affiliation: King's College London, MRC Centre for Neurodegeneration Research, Department of Neuroscience, Institute of Psychiatry, London, UK. Amy.Pooler@kcl.ac.uk
authors.forename: Amy M
authors.initials: AM
authors.lastname: Pooler
authors.forename: Alessia
authors.initials: A
authors.lastname: Usardi
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Evans
authors.forename: Karen L
authors.initials: KL
authors.lastname: Philpott
authors.forename: Wendy
authors.initials: W
authors.lastname: Noble
authors.forename: Diane P
authors.initials: DP
authors.lastname: Hanger
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D047389:Casein Kinase I / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D047389:Casein Kinase I; D038362:Glycogen Synthase Kinase 3